Summary The hippocampal formation is a structure of acute interest in neuroimaging, due to its crucial role in a wide spectrum of neurological disorders, including epilepsy, schizophrenia, and Alzheimer?s disease (AD). Three- dimensional mapping of the complex intra-hippocampal organization and subfield connectivity is of paramount importance, since different subregions of the hippocampus are known to exhibit selective and differential vulnerability to different neurological diseases, such as epilepsy and AD. Despite its central role in major neurological disorders, the internal laminar microstructure and subfield connectivity of the human hippocampus remain difficult to delineate with three-dimensional imaging techniques. The goal of this R01 proposal is to develop the first three-dimensional diffusion MRI computational atlas of the intact whole human hippocampus. The proposed atlas will build on key technical developments enabling combined high spatio-angular resolution diffusion MRI (dMRI) of the intact fixed hippocampus at 11.7T. The resulting atlas based on high angular resolution diffusion imaging (HARDI) data from multiple hippocampus specimens will provide delineation of human intra-hippocampal organization and circuitry in unprecedented microstructural detail. Further, current understanding of hippocampal circuitry and its disruption in disease is largely based on two-dimensional histological sections. The imaging platform and dMRI atlas established here will allow for the first time, investigation and three-dimensional mapping of region-specific changes in intra- hippocampal structure in normal aging and AD brains, providing details of hippocampal pathology in greater detail than previously possible. We will achieve these goals in four specific aims: (1) to develop accelerated three-dimensional diffusion MRI techniques for efficient sampling of the combined (k,q)-space, (2) to acquire combined high spatio-angular resolution 3D dMRI data of whole hippocampal specimens at 11.7T, (3) to construct a computational averaged HARDI atlas of the whole hippocampus using a diffeomorphic non-linear registration framework based on rotation-invariant HARDI features and Riemannian averaging, and (4) to investigate regional changes in intra-hippocampal structure in normal aging and AD. This project brings together innovative imaging techniques and computational analysis methods, that will allow development of the high-field dMRI atlas with microstructural detail. Upon completion, these goals will establish the first HARDI atlas of the human hippocampus, which will be an invaluable resource for neuroimaging studies, and provide significant insights to advance our understanding of hippocampal pathology in AD and aging.